Infections Are Implicated in Prostate Cancer

Viruses in the male genital tract and their effects on the reproductive system. N Dejucq, B Jegou. Microbiol Mol Biol Rev 2001 Jun;65(2):208-231. "In addition to providing an exhaustive account of the data available in these domains, this review focuses attention on the fact that the interface between endocrinology and virology has so far been poorly explored, particularly when major health, social and economical problems are posed."

Dejoucq - Microbiol Mol Biol Rev 2001 abstract / PubMed
Dejoucq / Microbiol Mol Biol Rev 2001 full article
Dejoucq - Microbiol Mol Biol Rev 2001 full article / PubMed Central

Meta-analysis of measures of sexual activity and prostate cancer. LK Dennis, DV Dawson. Epidemiology 2002 Jan;13(1):72-79. "The data suggest an elevated relative risk (RR) of prostate cancer among men with a history of sexually transmitted infections. This was observed with both random- and fixed-effects models (RR = 1.4; 95% CI = 1.2-1.7; N = 17 studies; heterogeneity P = 0.14), especially for syphilis (RR = 2.3; 95% CI = 1.3-3.9; N = 6; heterogeneity P = 0.47). Risk of prostate cancer is also associated with increasing frequency of sexual activity (RR = 1.2 for an increase of three times per week; 95% CI = 1.1-1.3; N = 12). However, these studies are heterogeneous (P < 0.001). Increasing number of sexual partners is also associated with prostate cancer (RR = 1.2 for an increase of 20 partners; 95% CI = 1.1-1.3; N = 16; heterogeneity P = 0.11). The data do not support associations with multiple marriages, age at first intercourse, or age at first marriage. These results indicate an association between prostate cancer and sexually transmitted infections, suggesting that infections may represent one mechanism through which prostate cancer develops."

Dennis & Dawson - Epidemiology 2002 abstract / PubMed

Demonstration of Epstein-Barr virus in carcinomas of various sites. S Grinstein, MV Preciado, P Gattuso, PA Chabay, WH Warren, E De Matteo, VE Gould. Cancer Res 2002 Sep 1;62(17):4876-4878. "Seven of 19 carcinomas showed strong EBV reactions in 5–30% of neoplastic nuclei. These cases included all grades of the Gleason classification ranging from well-differentiated adenocarcinomas (Fig. 1i) to hypernephroid and solid tumors. One of 7 carcinomas included foci of high-grade PIN, where convincing EBV reactive nuclei were seen in both basal and luminal cells (Fig. 1j) . All prostate carcinoma samples included foci of benign glandular hyperplasia, 3 of which showed sporadic positive nuclei; 10 normal prostate samples were negative. CD21 was not detected in epithelial cells. Our findings of EBV in prostatic carcinomas are entirely new. In these cases, the presence and possibility of EBV appeared unrelated to the degree of neoplastic differentiation because it was found in the entire range of tumors from those composed of regular glands to poorly differentiated and hypernephroid carcinomas. Interestingly, an architecturally and cytologically distorted carcinoma removed after androgen deprivation therapy showed abundant EBV-reactive cells. Also, in a single case of carcinoma, foci of high-grade PIN, acknowledged to be a precancerous proliferation, showed EBV immunostaining. This apparently low incidence may simply reflect the fact that the blocks containing carcinoma selected for this study were not chosen for the concomitant presence of PIN. Perhaps surprising was the frequent finding of scattered immunoreactive EBV cells in benign glandular hyperplasia. These results suggest that EBV may play a role in clearly proliferative but not necessarily malignant or premalignant lesions. In this context, our findings in the prostate parallel the above-described findings in nonprecancerous epithelial proliferations of the breast and colon. Conversely, the presence of EBV in dysplastic and precancerous proliferations of the prostate and breast underscores that EBV may indeed have an optional role in the development of carcinomas of these sites."

Grinstein / Cancer Res 2002 full article

Detection of human polyomaviruses and papillomaviruses in prostatic tissue reveals the prostate as a habitat for multiple viral infections. A Zambrano, M Kalantari, A Simoneau, JL Jensen, LP Villareal. Prostate 2002 Dec 1;53(4):263-276. "The paraffin-embedded archival samples gave variable, unsatisfactory results. Results from the fresh frozen samples, however, were consistent and were frequently positive for JCV and less frequent for BK virus DNA. ISH confirmed the presence of JCV DNA in prostatic glandular epithelium."

Zambrano - Prostate 2002 abstract / PubMed

Association between the presence of bacterial 16S RNA in prostate specimens taken during transurethral resection of prostate and subsequent risk of prostate cancer (Sweden). O Alexeyev, J Bergh, I Marklund, C Thellenberg-Karlsson, F Wiklund, H Gronberg, A Bergh, F Elgh. Cancer Causes Control 2006 Nov;17(9):1127-1133. 352 patients with benign prostate hyperplasia (BPH) who later developed prostate cancer (n = 171) and matched controls that did not progress to cancer (n = 181). "In 96/352 (27%) of the prostate tissue specimens 16S RNA were detected. Sequence analysis revealed Propionibacterium acnes as the predominant microorganism (23% of 16S RNA positive patients). The second most frequent isolate-Escherichia coli was found in 12 (12%) patients. The other isolates included Pseudomonas sp. (3 patients), Actinomyces sp. (2), Streptococcus mutans (1), Corynebacterium sp. (2), Nocardioides sp. (1), Rhodococcus sp. (1) Veillonella sp. (2). In P. acnes positive samples 62% exhibited severe histological inflammation versus 50% in the bacteria-negative group (p = 0.602). The presence of P. acnes in the prostate was associated with prostate cancer development (OR 2.17, 95% CI 0.77-6.95)."

Alexeyev et al - Cancer Causes Control 2006 abstract / PubMed

Human papillomavirus and Epstein Barr virus in prostate cancer: Koilocytes indicate potential oncogenic influences of human papillomavirus in prostate cancer. NJ Whitaker, WK Glenn, A Sahrudin, MM Orde, W Delprado, JS Lawson. Prostate 2013 Feb 15;73(3):236-241. "Both HPV type 18 and EBV gene sequences were identified in a high and approximately equal proportion of normal, benign, and prostate cancer specimens. These sequences were located in the nuclei of prostate epithelial cells. HPV associated koilocytes were identified in 24% of prostate cancer specimens."

Whitaker - Prostate 2013 abstract / PubMed

Evidence supporting the association of polyomavirus BK genome with prostate cancer. S Delbue, DV Matei, C Carloni, V Pecchenini, S Carluccio, S Villani, V Tringali, A Brescia, P Ferrante. Med Microbiol Immunol 2013 Dec;202(6):425-430. 124 consecutive patients, 56 with PCA and 68 with benign prostatic hyperplasia (BPH). "BKV-positive tissue specimens were found in 32.1 and 22.1 % of PCA and BPH patients, respectively; in PCA group the number of positive BKV specimens/patients was significantly higher than in BPH group (3.06 vs. 1.73, p = 0.02). JCV genome was found in the biopsies collected from 28.1 and 24.2 % of PCA and BPH patients, respectively, with no significant difference in the rate of JCV specimens/patients between PCA and BPH groups."

Delbue - Med Microbiol Immunol 2013 abstract / PubMed

Detection of human papillomavirus (HPV) DNA prevalence and p53 codon 72 (Arg72Pro) polymorphism in prostate cancer in a Greek group of patients. V Michopoulou, SP Derdas, E Symvoulakis, N Mourmouras, A Nomikos, D Delakas, G Sourvinos, DA Spandidos. Tumour Biol 2014 Dec;35(12):12765-12773. HPV DNA was detected in 8 out of 50 prostate cancer samples (16 %) versus 1 of 30 (3.33%) controls.

Michopoulou - Tumour Biol 2014 abstract / PubMed

Implication of high risk Human papillomavirus HR-HPV infection in prostate cancer in Indian population- A pioneering case-control analysis. N Singh, S Hussain, N Kakkar, SK Singh, RC Sobti, M Bharadwaj. Sci Rep 2015 Jan 16;5:7822. 95 prostate cancer cases and 55 benign prostate hyperplasia controls. "The data demonstrate HPV infection in 41% of prostate tumor biopsies and 20% in BPH. Subsequent PCR- based HPV typing using type - specific primers revealed 32% were infected with HPV type 16 whereas 6% were found to be positive for HPV type 18, while in BPH controls only 5% of the BPH controls were infected with HPV 16 and this difference was highly significant (p = 0.0004)."

Singh - Sci Rep 2015 full article / PubMed Central

Viral infections in prostate carcinomas in Chilean patients. H Rodríguez, J Levican, JP Muñoz, D Carrillo, ML Acevedo, A Gaggero, O León, T Gheit, O Espinoza-Navarro, J Castillo, I Gallegos, M Tommasino, F Aguayo. Infect Agent Cancer 2015 Sep 1;10:27. "HPV and JCPyV were not detected in any specimens (0/69, 0 %); whereas, BKPyV was detected in 6/69 PCas (8.7 %). We did not find a statistically significant association between the presence of BKPyV and age (p = 0.198) or Gleason score (p = 0.268). In addition, 2/6 (33 %) BKPyV positive specimens showed detectable levels of TAg transcripts."

Rodríguez - Infect Agent Cancer 2015 full article / PubMed Central
Rodríguez / Infect Agent Cancer 2015 full article

Polyomavirus Hominis 1(BK virus) Infection in Prostatic Tissues: Cancer versus Hyperplasia. A Taghavi, P Mohammadi-Torbati, AH Kashi, H Rezaee, M Vaezjalali. Urol J 2015 Sep 4;12(4):2240-2244. 60 prostate cancers and 60 of benign prostatic hyperplasia. "Viral DNA was identified in 9 patients (15%) with benign prostatic hyperplasia (BPH) and 17 patients (28%) with PCa (P = .076). In patients with PCa, viral DNA was observed more often in those with lower total Gleason scores (P = .045)."

Taghavi / Urol J 2015 full article landing page

Lack of detection of human papillomavirus DNA in prostate carcinomas in patients from northeastern Brazil. AP Araujo-Neto, H Ferreira-Fernandes, CM Amaral, LG Santos, AC Freitas, JC Silva-Neto, JA Rey, RR Burbano, BB Silva, FK Yoshioka, GR Pinto. Genet Mol Biol 2016 Mar;39(1):24-29. 0 / 104 prostate carcinoma cases were positive for HPV.

Araujo-Neto - Genet Mol Biol 2016 full article / PubMed Central
Araujo-Neto - Genet Mol Biol 2016 full article / Scielo

Adenovirus / SSBP2

Adenoviral E1B55K oncoprotein sequesters candidate leukemia suppressor sequence-specific single-stranded DNA-binding protein 2 into aggresomes. HB Fleisig, NI Orazio, H Liang, AF Tyler, HP Adams, MD Weitzman, L Nagarajan. Oncogene 2007 Jul 19;26(33):4797-4805. "Sequence-specific single-stranded DNA-binding protein 2 (SSBP2) is a candidate tumor suppressor for human acute myelogenous leukemia (AML). Inducible expression of SSBP2 causes growth arrest and partial differentiation in AML cells. Here, we report that the adenoviral oncoprotein E1B55K directly binds to endogenous SSBP2 protein and sequesters it into juxtanuclear bodies in adenovirally transformed human embryonic kidney (HEK) 293 cells... These data demonstrate that E1B55K targets the candidate leukemia suppressor SSBP2 and suggest that subverting its function may contribute to cell transformation by viral oncoproteins."

Fleisig - Oncogene 2007 abstract / PubMed

ssDNA-binding protein 2 is frequently hypermethylated and suppresses cell growth in human prostate cancer. JW Liu, JK Nagpal, W Sun, J Lee, MS Kim, KL Ostrow, S Zhou, C Jeronimo, R Henrique, W Van Criekinge, CS Moon, JA Califano, B Trink, D Sidransky. Clin Cancer Res 2008 Jun 15;14(12):3754-3760. "Quantitative methylation-specific PCR results showed that the SSBP2 promoter was hypermethylated in 54 of 88 (61.4%) primary prostate cancers versus 0 of 23 (0%) in benign prostatic hyperplasia using a cutoff value of 120. Furthermore, we found that expression of SSBP2 was down-regulated in primary prostate cancers and cancer cell lines. Hypermethylation of the SSBP2 promoter and its expression were closely associated with higher stages of prostate cancer."

Liu - Clin Cancer Res 2008 abstract / PubMed

Xenotropic Murine Leukemia Virus-Related Gammaretrovirus (XMRV)

Identification of a Novel Gammaretrovirus in Prostate Tumors of Patients Homozygous for R462Q RNASEL Variant. A Urisman, RJ Molinaro, N Fischer, SJ Plummer, G Casey, EA Klein, K Malathi, C Magi-Galluzzi, RR Tubbs, D Ganem, RH Silverman, JL DeRisi. PLoS Pathog 2006 March; 2(3): e25. A subset of patients with familial prostate cancer have a gene defect which is associated with increased susceptibility to certain infections. A high proportion of these patients have been infected with a retrovirus, named XMRV, which is similar to murine leukemia viruses (8/20 vs. 1/66). The Env protein sequence had the highest amino acid identity with the Env protein of an infectious MuLV isolated from a human small cell lung cancer line.

Urisman et al. PLoS Pathog 2006 full article / PubMed Central

Integration site preference of xenotropic murine leukemia virus-related virus, a new human retrovirus associated with prostate cancer. S Kim, N Kim, B Dong, D Boren, SA Lee, J Das Gupta, C Gaughan, EA Klein, C Lee, RH Silverman, SA Chow. J Virol 2008 Oct;82(20):9964-9977. "Balanced chromosome rearrangements, particularly translocations, are strongly associated with distinct tumor entities and may represent an initial event in oncogenesis. The common fragile site is another cancer-associated genomic feature that is frequently altered in non-virus-associated tumors. Both cancer breakpoints and common fragile sites are preferential integration targets for vector DNA, hepatitis B virus, and various DNA viruses, including human papillomavirus, Epstein-Barr virus, simian virus 40, and adeno-associated virus. These integration events may contribute significantly to the development of various types of cancers by disrupting the normal activity of tumor suppressor genes or proto-oncogenes in the vicinity. In the SCID-X1 gene-therapy trial wherein two patients received an MLV-derived vector and subsequently developed leukemia via activation of the LMO2 oncogene, the two integration sites targeted by the MLV-based vector reside within FRA11E, a common fragile site known to correlate with chromosomal breakpoints in tumors. Since XMRV integration in DU145 cells does not display a bias for cancer breakpoints and common fragile sites, the high XMRV integration preference seen in tumor samples for genomic regions with the highest frequencies of cancer breakpoints and common fragile sites is striking and likely represents a selection process. The key question of whether these integrated proviruses are an indirect consequence of genomic instability initiated by other genetic lesions or perhaps have a direct role in prostate carcinogenesis awaits further investigations." Integration also occurs in cytoband 16q22.1. "Two other integration sites, one each located in 11q13.4 and 19p13.2, are also in regions where high rates of chromosomal alterations have been observed in breast and prostate cancers."

Kim / J Virol 2008 full article
Kim - J Virol 2008 full article / PubMed

Prevalence of human gammaretrovirus XMRV in sporadic prostate cancer. N Fischer, O Hellwinkel, C Schulz, FK Chun, H Huland, M Aepfelbacher, T Schlomm. J Clin Virol 2008 Nov;43(3):277-283. "Forty percent (8/20) of familial prostate cancer patients homozygous for a mutation in RNase L (R462Q) were positive for XMRV, while the virus was rarely (1/66) detected in familial prostate cancer patients heterozygous for R462Q or carrying the wild type allele... XMRV-specific sequences were detected in one of 105 tissue samples from non-familial prostate cancer patients and from one of 70 tissue samples from men without prostate cancer. The two XMRV-positive patients were wild type or heterozygous for the R462Q mutation and thus carried at least one fully functional RNase L allele."

Fischer - J Clin Virol 2008 abstract / PubMed

XMRV is present in malignant prostatic epithelium and is associated with prostate cancer, especially high-grade tumors. R Schlaberg, DJ Choe, KR Brown, HM Thaker, IR Singh. Proc Natl Acad Sci U S A 2009 Sep 22;106(38):16351-16356. By quantitative PCR assay and immunohistochemistry (IHC) with an anti-XMRV specific antiserum, XMRV DNA was found in 6% and XMRV protein expression in 23% of 334 consecutive prostate cancers. There was no relation with a common polymorphism in the RNASEL gene.

Schlaberg - PNAS 2009 abstract / PubMed

Lack of evidence for xenotropic murine leukemia virus-related virus (XMRV) in German prostate cancer patients. O Hohn, H Krause, P Barbarotto, L Niederstadt, N Beimforde, J Denner, K Miller, R Kurth, N Bannert. Retrovirology 2009 Oct 16;6:92. 589 prostate tumor samples were all negative for XMRV, either DNA or RNA.

Hohn / Retrovirology 2009 full article
Hohn - Retrovirology 2009 full article / PubMed Central

The prostate cancer-associated human retrovirus XMRV lacks direct transforming activity but can induce low rates of transformation in cultured cells. MJ Metzger, CJ Holguin, R Mendoza, AD Miller. J Virol 2010 Feb;84(4):1874-1880. "Here we have used cultured fibroblast and epithelial cell lines to test the hypothesis that XMRV might have direct transforming activity but found only rare transformation events suggestive of indirect transformation, even when the target cells expressed the human Xpr1 cell-entry receptor for XMRV."

Metzger - J Virol 2010 abstract / PubMed

Detection of xenotropic murine leukemia virus-related virus in normal and tumor tissue of patients from the southern United States with prostate cancer is dependent on specific polymerase chain reaction conditions. BP Danielson, GE Ayala, JT Kimata. J Infect Dis 2010 Nov 15;202(10):1470-1477. "XMRV was detected in 32 (22%) of the 144 patients. Patients were significantly more likely to test positive for XMRV in both tumor and normal tissue rather than either alone (κ = 0.64). A positive result for XMRV was not significantly correlated with the R462Q polymorphism (P = .82) or clinical pathological parameters of prostate cancer, including Gleason score (P = .29)."

Danielson - J Infect Dis 2010 abstract / PubMed

Prevalence of human xenotropic murine leukemia virus-related gammaretrovirus (XMRV) in dutch prostate cancer patients. GW Verhaegh, AS de Jong, FP Smit, SA Jannink, WJ Melchers, JA Schalken. Prostate 2011 Mar 1;71(4):415-420. XMRV sequences were detected in 3 out of 74 (4%) prostate cancer specimens. "The number of XMRV containing cells was extremely low (1 in 600-7,000 cells). This was corroborated by the fact that XMRV could not be detected in consecutive tissue sections of the initial XMRV-positive cases."

Verhaegh - Prostate 2011 abstract / PubMed

No detection of xenotropic murine leukemia virus-related viruses in prostate cancer in sanandaj, west of iran. M Khodabandehloo, W Hosseini, MR Rahmani, MA Rezaee, MS Hakhamaneshi, B Nikkhoo, A Jalili. Asian Pac J Cancer Prev 2013;14(11):6929-6933. 63 prostate cancers and 100 benign prostate hyperplasias. "Results: Beta-actin sequences were successfully detected in the DNA extracts from all prostate tissues, confirming DNA extraction integrity. We did not detect XMRV in samples either from prostate cancers or benign prostate hyperplasias using XMRV specific primers."

Khodabandehloo / Asian Pac J Cancer Prev 2013 full article

The saga of XMRV: a virus that infects human cells but is not a human virus. M Arias, H Fan. Emerg Microbes Infect 2014 Apr;3(4):e. "Xenotropic murine leukemia virus-related virus (XMRV) was discovered in 2006 in a search for a viral etiology of human prostate cancer (PC). Substantial interest in XMRV as a potentially new pathogenic human retrovirus was driven by reports that XMRV could be detected in a significant percentage of PC samples, and also in tissues from patients with chronic fatigue syndrome (CFS). After considerable controversy, etiologic links between XMRV and these two diseases were disproven. XMRV was determined to have arisen during passage of a human PC tumor in immunocompromised nude mice, by activation and recombination between two endogenous murine leukemia viruses from cells of the mouse. The resulting XMRV had a xentropic host range, which allowed it replicate in the human tumor cells in the xenograft."

Arias & Fan - Emerg Microbes Infect 2014 full article / PubMed Central

Androgen-independent proliferation of LNCaP prostate cancer cells infected by xenotropic murine leukemia virus-related virus. K Kakoki, H Kamiyama, M Izumida, Y Yashima, H Hayashi, N Yamamoto, T Matsuyama, T Igawa, H Sakai, Y Kubo. Biochem Biophys Res Commun 2014 Apr 25;447(1):216-222. "It is now believed that XMRV is not the etiologic agent of prostate cancer... We found that XMRV-infected LNCaP cells can proliferate in the absence of the androgen dihydrotestosterone. Moreover, androgen receptor expression is significantly reduced in XMRV-infected LNCaP cells. Such alterations were not observed in uninfected and amphotropic MLV-infected LNCaP cells. This finding explains why prostate cancer cell lines are preferentially infected with XMRV."

Kakoki - Biochem Biophys Res Commun 2014 abstract / PubMed

See Also:

HPV in Men

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cast 04-13-16